Identification of loci associated with susceptibility to Mycobacterium avium subspecies paratuberculosis (Map) tissue infection in cattle

Johne's disease is a contagious bacterial infection of cattle caused by Mycobacterium avium ssp. paratuberculosis (Map). A previous genome-wide association analysis (GWAA) in Holstein cattle identified QTL on BTA3 and BTA9 that were highly associated (P < 5 x 10(-7)) and on BTA1, BTA16, and BTA21 that were moderately associated (P < 5 x 10(-5)) with Map tissue infection. The objectives of this study were to validate previous GWAA results in Jersey cattle (n = 57), Holstein cattle from the Pacific Northwest (PNW, n = 205) and a combined Holstein population from the PNW and the Northeast (PNW + NE, n = 423), and also identify new loci associated with Map tissue infection. DNA was genotyped using the Illumina BovineSNP50 BeadChip, and the PNW + NE data was also imputed to whole genome sequence level using Run4 of the 1000 Bull Genomes project with Beagle v 4.1 and FImpute. Cases were ileocecal node positive and controls were negative for Map by quantitative PCR (qPCR). Individuals were removed for SNP call rate < 90%, and SNP were removed for genotype call rate < 90% or minor allele frequency < 1%. For the Jersey, PNW, and PNW + NE, GWAA were conducted using an allelic dosage model. For the PNW and the PNW + NE, an additional efficient mixed-model association eXpedited (EMMAX) analysis was performed using additive, dominance and recessive models. Seven QTL on BTA22 were identified in the Jersey population with the most significant (P = 4.45 x 10(-6)) located at 21.7 megabases (Mb). Six QTL were associated in the PNW and the PNW + NE analyses, including a QTL previously identified on BTA16 in the NE population. The most significant locus for the PNW was located on BTA21 at 61 Mb (P = 8.61 x 10(-8)) while the most significant locus for the PNW + NE was on BTA12 at 90 Mb (P = 2.33 x 10(-5)). No additional QTL were identified with the imputed GWAA. Putative positional candidate genes were identified within 50 kb 5' and 3' of each QTL. Two positional candidate genes were identified in Jersey cattle, 1 identified in the PNW and 8 in the PNW + NE populations. Many identified positional candidate genes are involved in signal transduction, have immunological functions, or have putative functional relevance in Map entry into host cells. This study supported 2 previously identified SNP within a QTL on BTA16 and identified 16 new QTL, including 2 found in the PNW and the PNW+NE, associated with Map tissue infection.